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1.
J Biomol Struct Dyn ; 42(6): 2859-2871, 2024 Apr.
Article in English | MEDLINE | ID: mdl-37254302

ABSTRACT

Management of type 2 diabetes mellitus (T2DM) using dipeptidyl peptidase IV (DPP IV) inhibitors is gaining precedence as this enzyme plays an indispensable role in cleaving and inactivating peptides, such as glucagon-like peptide-1 (GLP-1), incretin hormones, and glucose-dependent insulinotropic polypeptide (GIP). There are several DPP IV inhibitors used to treat T2DM, but limited by side effects such as disturbed GIT, flu-like symptoms, etc. Thus, there is an urgent need for the development of novel and better DPP IV inhibitors for the management of the same. In the present study, we investigated the effect of new boronic acid-based thiazole compounds as DPP IV inhibitors. We used substituted anilines that were progressively modified through a multi-step synthesis and then chemically characterised. These molecules have good binding affinity and molecular interactions at the active site of the DPP IV enzyme. Two boronic acid-based molecules, i.e. PC06R58 and PC06R108, were used for the assessment of their in-vitro enzymatic activities. Both molecules (PC06108 and PC06R58) exhibited potent uncompetitive DPP IV enzyme inhibition at two different concentrations of 90.9 and 15.6 nM, respectively, compared to sitagliptin having an IC50 of 17.3 nM. Furthermore, the oral glucose tolerance test suggested significantly reduced blood glucose levels at 20 mg/kg of the body weight upon administration of PC06R58 and PC06R108 molecules in rats after glucose ingestion (2 g/kg of the body weight). The compounds showed satisfactory DPP IV inhibition. Furthermore, DPP IV inhibitory activity and acceptable pre-ADME/Tox profile indicate it is a lead compound in this novel class of DPP IV inhibitors.Communicated by Ramaswamy H. Sarma.


Subject(s)
Diabetes Mellitus, Type 2 , Dipeptidyl-Peptidase IV Inhibitors , Hyperglycemia , Rats , Animals , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Glucose , Diabetes Mellitus, Type 2/drug therapy , Hyperglycemia/drug therapy , Hyperglycemia/chemically induced , Gastric Inhibitory Polypeptide/metabolism , Gastric Inhibitory Polypeptide/therapeutic use , Body Weight , Blood Glucose/metabolism , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/therapeutic use
2.
J Drug Target ; 28(1): 11-22, 2020 01.
Article in English | MEDLINE | ID: mdl-30798636

ABSTRACT

Neuropathic pain (NeP) is a complex chronic pain condition associated with nerve injury. Approximately, 7-10% of the general population across the globe is suffering from this traumatic condition, but the existing treatment strategies are inadequate to deliver pain relief and are associated with severe adverse effects. To overcome these limitations, lot of research is focussed on developing new molecules with high potency and fewer side effects, novel cell and gene-based therapies and modification of the previously approved drugs by different formulation aspects. Nanomedicine has attracted a lot of attention in the treatment of many diverse pathological conditions because of their unique physiochemical and biological properties. In this manuscript, we highlighted the emerging role of nanomedicine in different therapies (drug, cell and gene), also we emphasised on the challenges associated with nanomedicine such as development of well-characterised nanoformulation, scaling of batches with reproducible results and toxicity along with this we discussed about the future of nanomedicine in the treatment of neuropathic pain.


Subject(s)
Neuralgia/therapy , Cell- and Tissue-Based Therapy/methods , Central Nervous System Diseases/drug therapy , Central Nervous System Diseases/physiopathology , Chemotherapy, Adjuvant/methods , Drug Combinations , Drug Delivery Systems , Genetic Therapy/methods , Humans , Medical Marijuana/therapeutic use , Nanomedicine/methods , Neuralgia/drug therapy , Peripheral Nervous System Diseases/drug therapy , Peripheral Nervous System Diseases/physiopathology
3.
Xenobiotica ; 50(7): 815-821, 2020 Jul.
Article in English | MEDLINE | ID: mdl-31755347

ABSTRACT

Recent approvals of beta-lactamase inhibitor (BLI) drug in combination with cephalosporins/penems have provided the right impetus for novel BLIs. One important research question, hitherto not addressed, is pertaining to the relevance of preclinical pharmacokinetics for pairing the antibiotic with existing/novel BLI.Two BLI combination drugs: (a) approved (i.e. ceftazidime/avibactam); (b) clinical development (i.e. cefepime/zidebactam) were explored to provide insights to address the research question.Individual intravenous dosing of ceftazidime, avibactam, cefepime and zidebactam was done at 1 mg/kg by intravenous route in Balb/c mice and Wistar rats. Serial blood samples were collected and analysed by LC-MS/MS method.Examination of the ratios of pharmacokinetic parameters (CL, VSS and T1/2) for individual drugs in combinations (for instance, CL (ceftazidime)/CL (avibactam); CL (cefepime)/CL (zidebactam)) suggested that the pharmacokinetic data gathered in rats were generally within 0.5- to 2-fold; but mouse data revealed larger disparity for VSS (0.11- to 8.25-fold) or CL (0.49- to 4.03-fold).The observed ratio for CL/VSS observed in rats agreed with corresponding human ratios for the pairwise comparison of the individual drugs in the combinations.Retrospectively, current pharmacokinetic findings suggest rat pharmacokinetic data may aid the combination of BLI with an appropriate antibiotic.


Subject(s)
Azabicyclo Compounds/metabolism , Ceftazidime/metabolism , beta-Lactamase Inhibitors/metabolism , Animals , Cyclooctanes , Drug Combinations , Mice , Microbial Sensitivity Tests , Piperidines , Rats , Rodentia
4.
Eur J Pharm Sci ; 130: 107-113, 2019 Mar 15.
Article in English | MEDLINE | ID: mdl-30633968

ABSTRACT

Saroglitazar, a PPAR αÒ® agonist, is currently undergoing global development for the treatment of NASH and other indications. Saroglitazar showed CYP2C8 inhibition in human liver microsomes (IC50: 2.9 µM). The aim was to carry out drug-drug interaction (DDI) studies in Wistar rats using saroglitazar (perpetrator drug) with five CYP2C8 substrates. Also, the in vitro CYP2C8 inhibitory potential of saroglitazar in rat liver microsomes (RLM) was evaluated to justify use of preclinical model. The oral pharmacokinetics of various CYP2C8 substrates; montelukast, rosiglitazone, pioglitazone, repaglinide and intravenous pharmacokinetics of paclitaxel was assessed in the presence/absence of oral saroglitazar (4 mg/kg) in Wistar rats. A separate study was performed to assess the oral pharmacokinetics of saroglitazar. Serial blood samples were collected from all studies and the harvested plasma were stored frozen until bioanalysis. LC-MS/MS was used for the analysis of various analytes; concentration data was subjected to noncompartmental pharmacokinetic analysis. Statistical tests (unpaired t-test) were employed to judge the level of DDI. Generally, the pharmacokinetics of CYP2C8 substrates was not affected by the concomitant intake of saroglitazar as judged by the overall exposure (AUC0-last and AUC0-inf) and elimination half-life. The CYP2C8 IC50 of 4.5 µM in RLM for saroglitazar, supported the use of rats for this DDI study. In conclusion, pharmacokinetic data of diverse CYP2C8 substrates suggested that coadministration of saroglitazar did not cause clinically relevant DDI.


Subject(s)
Cytochrome P-450 CYP2C8 Inhibitors/pharmacokinetics , Cytochrome P-450 CYP2C8/metabolism , Microsomes, Liver/metabolism , Phenylpropionates/pharmacokinetics , Pyrroles/pharmacokinetics , Acetates/pharmacokinetics , Animals , Carbamates/pharmacokinetics , Cyclopropanes , Dose-Response Relationship, Drug , Drug Interactions/physiology , Humans , Male , Microsomes, Liver/drug effects , Paclitaxel/pharmacokinetics , Pioglitazone/pharmacokinetics , Piperidines/pharmacokinetics , Quinolines/pharmacokinetics , Rats , Rats, Wistar , Rosiglitazone/pharmacokinetics , Sulfides
5.
Neurosci Lett ; 674: 162-170, 2018 05 01.
Article in English | MEDLINE | ID: mdl-29559419

ABSTRACT

Despite considerable advances in understanding mechanisms involved in chronic pain, effective treatment remains limited. Astaxanthin, a marine natural drug, having potent anti-oxidant and anti-inflammatory activities is known to possess neuroprotective effects. However, effects of astaxanthin against nerve injury induce chronic pain remains unknown. Overactivity of glutamatergic NMDARs results in excitotoxicity which may participate in astrocytic and microglial activation during pathology which further contribute to the development of neuropathic pain. In this study, we investigate the effects of astaxanthin on oxido-inflammatory and NMDA receptor down-regulation pathway by using in-silico, in-vitro and in-vivo models of neuropathic pain. In-silico molecular docking study ascertained the binding affinity of astaxanthin to NMDA receptors and showed antagonistic effects. Data from in-vitro studies suggest that astaxanthin significantly reduces the oxidative stress induced by the lipopolysaccharides in C6 glial cells. In male Sprague dawley rats, a significant attenuation of neuropathic pain behavior was observed in Hargreaves test and von Frey hair test after astaxanthin treatment. Findings from the current study suggest that astaxanthin can be used as potential alternative in the treatment of chronic neuropathic pain. However, more detailed investigations are required to further probe the in-depth mechanism of action of astaxanthin.


Subject(s)
Analgesics/administration & dosage , Behavior, Animal/drug effects , Neuralgia/drug therapy , Neuralgia/metabolism , Animals , Antioxidants/administration & dosage , Cell Survival , Cells, Cultured , Disease Models, Animal , Hyperalgesia/drug therapy , Inflammation/chemically induced , Inflammation/metabolism , Lipopolysaccharides/administration & dosage , Male , Molecular Docking Simulation , Oxidative Stress/drug effects , Pain Threshold/drug effects , Rats, Sprague-Dawley , Receptors, N-Methyl-D-Aspartate/chemistry , Receptors, N-Methyl-D-Aspartate/metabolism , Xanthophylls/administration & dosage , Xanthophylls/chemistry
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